Generation and Reactivity of C(1)‐Ammonium Enolates by Using Isothiourea Catalysis

Abstract C(1)‐Ammonium enolates are powerful, catalytically generated synthetic intermediates applied in the enantioselective α‐functionalisation of carboxylic acid derivatives. This minireview describes the recent developments in the generation and application of C(1)‐ammonium enolates from various precursors (carboxylic acids, anhydrides, acyl imidazoles, aryl esters, α‐diazoketones, alkyl halides) using isothiourea Lewis base organocatalysts. Their synthetic utility in intra‐ and intermolecular enantioselective C−C and C−X bond forming processes on reaction with various electrophiles will be showcased utilising two distinct catalyst turnover approaches.

Seminal work by Wynberg demonstrated C(1)-ammonium enolatei ntermediates could be accessedb yd irect nucleophilic addition of aL ewis base catalysto nto ak etene startingm aterial. [9] However,k etenesa re typically unstable to long-terms torage and are pronet od imerisation.A lternative methods have focusedo nt he in situ generation of C(1)-ammonium enolates from bench stable carboxylic acid derivatives. These strategies all rely on the acylationo ft he Lewis base by ac arboxylic acid derivative,f ollowed by deprotonation of the subsequent acyl ammonium ion to give the C(1)-ammoniume nolatei ntermediate (Scheme 1). Carboxylic acidc hlorides (through in situ ketene formation), [10] carboxylic acids (via derivatisation to an activatede ster, [11] or mixed anhydride), [12] homoanhydrides [13] and electron deficient aryl esters have been shown to be effective bench stable starting materials for C(1)-ammonium enolate generation. [14] The nucleophilicenolatecan engage in stereose-lectiveC ÀCa nd CÀXb ondf ormation on reactionw ith an electrophile, giving a-functionalisedc arbonyl compounds at the carboxylic acid oxidation level followingc atalyst turnover. Owingt ot he mild basic reactionc onditions, enolisable tertiary stereogenic centres can be formed in high enantiopurity with good functional group tolerance. Therefore, tertiarya mine catalysis via C(1)-ammonium enolatei ntermediates is an attractive approachfor the synthesis of complex molecules containing afunctionalised carboxylic acid, esters and amide functionality, motifs that are found in many biologically relevant molecules. [15]  The catalytic reactivity of C(1)-ammonium enolates is governed by two distinct catalyst turnover approaches (Scheme 2). Traditional strategies effected catalystt urnover via an intramolecular lactonisation/lactamisation approach (Scheme 2a). Mechanistically,t his involves N-acylation of the Lewis base by the carboxylica cid derivative (anhydride, ketene) to give an acyl ammonium ion pair.T he C(2)-protons become more acidic due to the electron withdrawing nature of the cationic nitrogen atom, with subsequentd eprotonation giving the keyz witterionic C(1)-ammonium enolatei ntermediate.R eaction with a suitable electrophile (to exemplify,aM ichael acceptor) forms the functionalised acyl ammonium intermediate. Finally,i ntramolecular catalyst turnover by the generated anion is used to releaset he product and regenerate the catalyst. This turnover approachh as found widespread application for the synthesis of chiral heterocycles in formal cycloadditionp rocesses with high stereocontrol. [5b] Ak ey requirement in this strategy is the need for al atent nucleophilic component to be incorporated within the electrophile that is used to turnover the catalyst via intramolecular cyclisation. Although powerful, this approach also represents af undamentall imitation in these processes where only cyclic products can be formed. When using electron deficient aryl ester precursors, an alternative catalystt urnover pathwayc an be accessed (Scheme 2b). [16] In this case, the aryloxide anion, released upon N-acylationo ft he Lewis base, can react with the post-reactiona cyl ammonium ion. This approach presentsastrategy for the formation of acyclic a-functionalised products at the carboxylic acid oxidation level, significantly broadeningt he potential applicabilityo fC (1)-ammonium enolates in enantioselective catalysis.
Isothiourea Lewis base organocatalysts [8] such as tetramisole (TM), [17] benzotetramisole (BTM) and HyperBTM, [18,19] have found widespread application in C(1)-ammonium enolate catalysis, imparting high degrees of diastereo-and enantioselectivity ( Figure 2a). The enantiocontroli nvolving C(1)-ammonium enolates is governed by selectivef ormation of the (Z)-enolate and a1 ,5-O···S interaction (characterised as n O to s* C-S )b etween the enolate oxygen anion and Sa tom of the catalyst, [20] which restricts the conformationalf reedom of this intermediate ( Figure 2b). The stereodirecting phenyl group effectively blockst he Si faceo ft he C(1)-ammonium enolate, with preferential reaction with an electrophile occurring on the less hindered Re face. [21] This review will survey selected recent advances in the generationa nd reactivityo fC (1)-ammonium enolatesu sing isothiourea catalysis. For ac omprehensive discussiono np rocesses developedp rior to 2014, readers are directed to at horough previous review. [5b] New concepts that allow access to C(1)-ammonium enolates from different startingm aterials will be showcased. The application of both catalyst turnover methodologies highlighted in Scheme 2inc ombination with new electrophilicp artners for the synthesis of cyclic and acyclic a-functionalised carboxylic acids, esters and amides will be featured. Key currentc oncepts, including the development of more sustainable processes that do not requiree xcesss toichiometric additives, will also be discussed. Advances in substrate scope will be highlighted, with particularf ocuso nt he a-substituent of the enolatep recursor,w hich has been traditionally limited to mono-substitution with aryl, heteroaryl, alkenyl or heteroatom groups.
This intramolecular protocol was extended to the catalytic enantioselective synthesis of pyrrolizines (Scheme 4). [23] Using commercially available catalyst( R)-BTM 9 (5 mol %), ar ange of pyrrole-derived enone-acids 8 were convertedt od ihydropyranones 10.F ollowing in situ ring-opening with suitable amine and alcoholn ucleophiles, the more stable pyrrolizine carboxylate derivatives 11 could be obtained in good to high yields (53-99%)w ith excellent diastereo-and enantioselectivity (all ! 94:6 dr, ! 98:2 er). Notably,n oc ompeting Friedel-Crafts acy- Scheme3.Michael addition/lactonisation for the synthesis of (a) syn-2,3-tetrahydrofurans and (b) syn 3,4-tetrahydrofurans. (S)-TM·HCl. lation or b-elimination of the pyrrole was observed in the presence of am ixed anhydride or acyl ammonium ion species. DFT calculations using the M06-2X functional werea pplied to compute the energy profiles of reaction pathways of the (Z)-C(1)ammonium enolate to form the cis-a nd trans-isomers of dihydropyranones 10.S ignificantly,f ormation of the observed cis isomer was computed to be both kinetically and thermodynamically favoured. Interestingly,a na lternative pathway involvingt he (E)-C(1)-ammonium enolate was characterised but had as ignificantly higherb arrier.O ther observations included ac alculated1 ,5-O···S distance to be shorter than the sum of the van der Waals radii found in all intermediates from the (Z)enolateo nwards to catalyst dissociation, highlighting this nonbondingi nteraction.
The previouse xamples involve ac ommon 5-exo-trigr ing closure to give the corresponding heterocyclic product. Rarer is the related 6-exo-trig ring closure and there are only al imited number of examples of this transformation, all of which use cinchonaa lkaloid catalysts. [11b,e,g] The Michael addition/lactonisation methodology was therefore appliedf or the synthesis of chromenones via a6 -exo-trig cyclisation. [24] Treatmento f enone-acids 12 with pivaloyl chloride and subsequent addition of tetramisole 7 (5 mol %) at 0 8Cp rovided as uite of cis-chromenones 13 in excellent yield, diastereomeric ratio (dr) and enantiomeric ratio (er) (Scheme 5a). During detailed temporal studies it was observedt hat base-catalysed epimerisation was in operation, leading to increased diastereomeric ratio and lower enantiomeric ratio upon extended reactiont imes. To circumventt his problem ap ost-reaction acidic aqueous work-up was incorporated to enable isolation of the products in high dr and er.T he observedd iastereo-and enantioselectivity of the Michael addition step can be rationalised by as implistic model where the 1,5-O···S interaction restricts the conformation of the (Z)-enolate with Michael addition occurring anti-t ot he stereodirectingu nit of the catalystv ia pre-transitions tate assembly TS-I (Scheme 5b).
In 2014, the Michael addition/lactonisation methodology was incorporated into as equence for the synthesis of di-, triand tetrasubstituted pyridines (Scheme 8). [30] Following the formal [4+ +2] cycloadditionb etween (phenylthio)acetic acids 27 and a,b-unsaturated ketimines 22 catalysed by achiral isothiourea DHPB 28 to give dihydropyridinone products 29, treatment with m-CPBA yielded the desired sulfoxides 30, which underwent elimination on warming to room temperature. The pyridones 31 were heateda t8 0 8Ct op rovide the pyridine products 32.H owever,a ttempts to carry out ao nepot protocol were unsuccessful, yielding complex mixtures. Typically, a,a-disubstituted acetic acid derivatives are unproductive starting materials for C(1)-ammonium enolateg eneration using isothioureas.N otably in this case, a,a-disubstituted (phenylthiol)acetic acids are tolerated, enabling substitution in the 5-position of the pyridine. An advantage of this methodology is the 2-tosyl functional handle in the product,w hichw as utilised in as eries of derivatisations(Heck, S N Ar).
vation and Michael addition/lactonisation of pyrrole acetic acid 37 with ar ange of trichloromethyl enones 38,f ollowed by addition of an appropriate alcohol or amine nucleophile gave ring-opened di-ester and di-amide products 39.T he nucleophilic pyrrole unit could be exploitedi nas eries of Friedel-Crafts acylation derivatisations. Treatment of isolated diesters 39 with boron tribromide yieldedf unctionalised dihydroindolizine 40 products whilst maintaining the diastereo-and enantiopurity.
Building upon this precedent, ao ne-pot tandem sequential protocolw as developed for the synthesis of enantioenriched tetrahydroindolizine derivatives 43 containing three stereogenic centres (Scheme 10 b). [35] Michael addition/lactonisation reaction of 2-pyrrole acetic acid 37 with Michael acceptors bearing an electron withdrawingg roup 41,f ollowedb yr ing opening by an appropriate amine or alcoholn ucleophile,g ave dicarbonyl intermediate 42.I ti sp roposed these can undergo spontaneous cyclisation of the pyrrole moiety onto the electrophilic ketone through chair-like transition state TS-II,y ielding the tetrahydroindolizines 43 in high diastereo-and enantioselectivities. Key to the success of the protocol employing trifluoromethyl enone Michael acceptors was choice of reaction media; reactions carried out in acetonitrile and dichloromethane lead to am ixture of the desired product and by-products from competing [2+ +2] formal cycloaddition and product isomerisation. Screening of 25 different solvents demonstrated that ethereal solvents were optimal for selectivity for the desired product, with diethyl ether,c yclopentylmethyl ether (CPME), ethyl acetate and isopropyla cetate giving best results.
Pericàsa nd co-workersd emonstrated the first use of ap olystyrene-supported isothiourea 46 in av ariety of Michael addition/cyclisation reactions (Scheme 11). [36] First, the catalystw as tested in ab enchmark Michael addition/lactamisation reaction of carboxylic acids with chalcone-derived tosylimines (Scheme 11 a), [36a] previously reported by Smith and co-workers. [12b] Notably, ortho-substitutedp henyla cetic acid derivatives such ortho-tolyl 44 gave the corresponding dihydropyridone product 47 with enhanced diastereoselectivity (93:7 dr) compared to the corresponding reaction with BTM 9 (50:50 dr). It was proposed that substitution of the 3-position of the catalyst to enable immobilisation destabilises the transition state leading to the minor cis diastereoisomer.D uring the optimisation of this process, it found that all the reagents could be combined from the start of the reaction and that premixing the carboxylic with pivaloyl chloride was not necessary,l eading to as implified protocol.I mportantly,s ix consecutive cycles were performed with constant stereoselectivity and yield, exemplifying the recyclability of catalyst 46.Acontinuous flow protocol was also developed through as equential preactivation and reaction set-up, which allowed 4.4 go fp roduct to be obtained. This protocol was also applied in Michael addition/lactamisation reactions using saccharin-derived sulfonyl imine electro-philes. In 2017, Pericàsa nd co-workerse xtended the use of polystyrene-supported isothiourea 46 to Michael addition/lactonisation reactions (Scheme 11 b). [36b] Carboxylica cids 14 underwents mooth reactionw ith alkylidene pyrazolones, isatin derivatives and alkylidene thiazolonest og ive the corresponding polycyclic dihydropyranopyrazolones (49, 50)a nd dihydropyranothiazolones 51.
The Michael addition/lactonisation cascade methodology was employedb yt he groups of Smith and Hähner to enable the direct enantioselective functionalisation of as ilicon oxide supported self-assembled monolayer (Scheme 12). [37] Reaction of surface-bound trifluoromethyl enone 52 with 4-fluorophenyl acetic acid 53 catalysed by HyperBTM 18 allowed the preparation of the modified surface 54,w ith chiral AFM used to probe the enantioinduction on the surface.
Whilst these strategies employing carboxylic acid precursors have been applied for the synthesis of ar ange of chiral heterocycles, one drawback is the use of stoichiometric (often multiple equivalents) of activating agent and auxiliary base to prepare areactive acylatingagent in situ. In addition, the by-products generated from these processes (such as pivalic anhydride from pivaloyl chloride) can be difficult to separatefrom the desired products. [12a] Considering this, Smith and co-workers reported an alternative methodo fg enerating C(1)-ammonium enolates from N-acyl imidazoles under acidic conditions (Scheme 13 a). [38] In situ protonation of the N-acyl imidazole enables significantly enhanced catalystacylation (utilising the recognised "imidazolium effect") [39] whilst the expected imidazole by-product is non-toxic and water soluble and can be readily removedf rom reaction mixtures. This wasd emonstrated in initial equilibrium studies between N-acyl imidasole 55 and( R)-BTM·HCl 56,which led to rapid equilibration to N-acyl ammonium ion pair 57 and imidazole with K exp = 0.59 (Scheme 13 b). In contrast,n oc atalyst acylation was observed when acyl imidazole 55 and free base (R)-BTM 9 were mixed. This was then exploited in formal [4+ +2] cycloadditions with ar ange of Michael acceptors 59 (trifluoromethyl enones, chalcone-derived ketimines and saccharin-derived ketimines). Comprehensive mechanistic investigations using 19 F{ 1 H} NMR reactionm onitoring were carried out to provide further insighti nto the developed methodology. Kinetica nalysesi ncluding reaction prog-ress kinetic analysis( RPKA) [40] and variable time normalisation analysis( VTNA) [41] techniques were undertaken to determine the order of each component. The catalyst, N-acyl imidazole and enone weref ound to be first order,w hilst an inverse secondary kinetic isotope effect was observed (k H /k D = 0.75), indicating the Michael addition step was turnover limiting (Scheme 14 a). [42] Notably,s ame excess experimentsf ound that the imidazole formed during the progress of the reactioni nhibited the reaction rate. Based upon the information gained from the mechanistic studies, ac atalytic cycle has been proposed (Scheme 14 b). In an extensiono fa vailable bench stable enolate precursors, the use of aryl esters in the Michael addition/lactonisation approachh as been reported (Scheme 15). [43] Te tramisole 7 effectively catalyses the reactiono f2 ,4,6-trichlorophenyl esters 67 with trifluoromethyl enones 68.
In 2019, Song and co-workers, inspired by previous work by Lectka using cinchonaa lkaloid catalysts, [44] developed an elegant methodt og enerate isothiouronium enolates from a-d iazoketones for the first time in combination with visible light photoactivation (Scheme 16). [45] Excitation of the diazoketone initiates nitrogen extrusion to generate the a-keto carbene intermediate which can undergo [1,2]-migrationt oa fford the ketenei ntermediate (Scheme16a). Significantly,t his allows accesst od isubstituted ketenes, and therefore disubstituted C(1)-ammonium enolates, whichh ad previously been limited in this area of research using isothioureas. This strategy was appliedi nt he enantioselectiveM ichael addition/lactamisation of ketenes, generated from a-diazoketones 70 and blue LED photoactivation, and aurone derived imine Michael acceptors 71.T he reactionw as catalysed by an ewly designed isothiourea catalyst 72,enablingthe construction of polycyclic benzofuran derivatives containing an all carbon quaternary stereogenic centre 73 (Scheme 16 b).

Intermolecular reactions:M iscellaneous formalcycloadditions
Smith and co-workersr eported the formal [3+ +2] cycloaddition of homoanhydrides 76 with oxaziridine electrophiles 77 for the enantioselective preparation of oxazolidine-4-ones (Scheme 17 a). [47] Using racemic oxaziridines 77 low diastereoselectivities were observed (up to 59:41 dr). Further investigations revealed the diastereoselectivity of the reaction decreasedo ver time (80:20 to 60:40 dr), indicating ak inetic resolution process was occurring, with one enantiomer of the oxaziridine being consumedf aster than its counterpart. Employing an enantioenriched oxaziridine 77 enabled the synthesis of a range of anti-oxazolidin-4-ones 78 in high yield with excellent stereocontrol (Scheme 17 b). However,u sing the opposite enantiomer of the catalyst could only afford syn-products in 80:20 dr due to mismatched effects. In 2015, Chi and co-workers reported the isothiourea-catalysed formal [3+ +2] cycloaddition of C(1)-ammonium enolates generated from mono-chloro substituted cyclobutenones 80 and ar ange of azomethine imines 81 for the synthesis of highly functionalised enantioenriched pyrazolidinone derivatives 82 (Scheme 18 a). [48] This is the first example of the generation of aC (1)-ammonium enolate from ac yclobutanone starting material. It is postulated that the mechanism proceeds via 1,2-addition of the isothiourea Lewis base to the mono-chloro substituted cyclobutenone,b reaking the conjugation of the startingm ateriala nd generating anionic oxy-intermediate (Scheme 18 b). Considering the (Z)-configuration of the alkene and the absolutec onfiguration at C(2) in product 82,atransrelative stereochemistryb etween the chloro and isothiouronium substituents of this intermediate is likely but not defined in the original manuscript. This can undergo strain-release driven carbon-carbonb ond cleavage throughe lectrocyclic conrotatory 4per ing-opening to give the dienolate. The resultant dienolate reacts regioselectively through the a-carbon, consistentw ithp revious work in this area. [12g] Notably,u nsubstituted, methyl-substituted and dichloro-substituted cyclobutenones were unreactive in this protocol. Significantly,t his process does not generate stoichiometric by-products in the generation of the C(1)-ammonium enolate, although 10 equiva-Scheme17. Isothiourea-catalysed formal [3+ +2] cycloadditions with (a) racemic oxaziridinesa nd (b) enantioenriched oxaziridines.T s= tosyl.

Intermolecular reactions:S ynergistic catalysis
The unification of C(1)-ammonium enolate intermediates with catalytically generated reaction partnersi nc ooperative or synergistic processes has been targeted in the pursuit of novel reactivity modes. In 2002, in ap ioneering contribution, Lectka and co-workersi ntroduced this concept in the diastereo-and enantioselective synthesis of b-lactams 93 through dual Lewis base/Lewis acid catalysis (Scheme 21 a). [52] Ac inchona alkaloid-based Lewis base catalyst was employedf or the in situ generation of the C(1)-ammonium enolatei ntermediate from a ketene precursor 91,w hilst an achiral Lewis acid catalyst (In(OTf) 3 )w as proposed to increase the electrophilicity of the imine electrophile 92.S ubsequently,L ectka, and others, have demonstrated the utility of C(1)-ammonium enolates combined with variousm etal Lewis acids. [53] In another significant development, Leckta demonstrated the advantageous use of nickel, palladium and platinum Lewis acid catalysts in the reaction of C(1)-ammoniume nolates with o-chloranil 95 for enantioselective a-hydroxylation, with palladium giving optimal results (Scheme 21 b). [54] In this case, rather than simple coordination to the electrophile to increaser eactivity,i ti sp roposed that the Lewis acid cocatalyst complexest ot he C(1)-ammonium enolate. This leads to stabilisation of this intermediate, increasingi ts concentrationi nt he reaction mixture, therefore enhancing the rate of reaction.
Transitionm etalsa re capable of catalysing ab road range of transformationsa nd have shown to be compatible with various organocatalysts in dual catalytic processes. [55] Inspiredb y the work of Lectka, Snaddona nd co-workers reported the first synergistic isothiourea/transitionm etal catalysis process involving C(1)-ammoniume nolates intermediates in 2016 (discussed in section3.2). [56] Building on this precedent, Gong andc oworkers demonstratedt he combination of an isothiourea Lewis base and copperc atalytic cycles for the enantioselective a-propargylation of carboxylic acids (Scheme22a). [57] Uniting the transient C(1)-ammonium enolate simultaneously with an electrophilic copper-allenylidene complexg enerated through the known decarboxylation of propargylic ester derivatives enabled the formation of intermediate acyl ammonium, [58] which could undergo lactamisation to form 3,4-dihydroquinolin-2ones. Using ac hiral copperc omplex generated in situ from [Cu(MeCN) 4 ]PF 6 ]a nd pyridinyl bis(oxazoline) ligand 99,t he authors reported the formal [4+ +2] annulation of ar ange of carboxylic acids 14 and 4-ethynyl dihydrobenzooxazinones 98 to give the 3,4-dihydroquinolin-2-one products 100 with excellent stereoselectivities (Scheme 22 b). Lower diastereoselectivities were observed when achiral ligands were used, or when the opposite enantiomer of isothiourea wase mployed ((S)-BTM 9), indicating the matchedc hirality of each catalysti sc rucial for stereocontrol. Wu and co-workersh ave also developed ar elated a-propargylation/lactamisationc ascade using pivaloyl chloride to generate ar eactive mixed anhydride in situ. [59] Inspired by work by Shi on the copperc atalysed a-amination of methyl esters, [60] Gong and co-workers rendered this transformation enantioselective through the developmento fa cooperative Lewis base and copper catalysis approach (Scheme 23 a). [61] Ar ange of pentafluorophenyl esters 101 underwents mooth a-amination with N,N-di-tert-butyldiaziridinone 102 to give hydantoin products 103 with excellent enantioselectivity when subjected to chiral (R)-iPr BTM 34 and Cu I phosphine complex.K ey to the successo ft his processw as judicious choice of the electron deficienta ryl ester.W hen pentafluorophenyl ester was used, significantly higher yields (and enantioselectivities)w ere observed compared to the corresponding para-nitrophenyl ester,a no bservation first reported by Snaddona nd co-workersi n2 016. [56] Ar ange of coppers alts were found to work efficiently( CuCl, CuBr,C uI), however the phosphine ligand was required to enhancet he catalytic activity of Cu I .T he proposed mechanism involves NÀNb ond cleavage of N,N-di-tert-butyldiaziridinone by the Cu I catalystt og enerate af our-membered Cu III species which is in equilibrium with aC u II radical species( Scheme 23 b). Simultaneously,t he Lewis base could undergo acylation on reaction with the pentafluorophenyl ester,a nd subsequentd eprotonation of the acyl ammoniumi on would form the transient C(1)-ammonium enolate intermediate. Union of the two catalytic cycles through single electron reactiono ft he C(1)-ammonium enolate with Cu II -intermediate furnishes the radical intermediate. Subsequent cyclisation regenerates both copperc atalyst and chiral isothiourea and give the product hydantoin. To confirm this Cu I /Cu II mechanistic hypothesis, electron paramagnetic resonance (EPR) spectroscopy studies indicated the formation of a nitrogen radical when N,N-di-tert-butyldiaziridinone 102 was treated with CuCl-P(nBu) 3 ,w hich was also observed during monitoring of the reaction mixture. Due to the complexe quilibria of copper catalysis, an alternative Cu I /Cu III pathway via reaction of an acyl ammonium ion with Cu III speciesf ollowed by reductiveelimination cannot be completely ruled out.
Gong and co-workershave also reported the seminalcatalytic generation of C(1)-ammonium enolates from the simple feedstock chemicals alkyl halidesand carbon monoxide (CO). [62] The authorsh ypothesised that oxidativea ddition of the palladium catalysti nto the CÀXb ond of an alkyl halide, followed by CO insertion would give an acyl palladium intermediate (Scheme 24 a). Underb asic reaction conditions ak etene intermediate could be accessed and interceptedb yaLewis base to generatet he C(1)-ammonium enolate. The authors demonstrated this protocol in ao ne-pot palladium catalysedc arbonylation-Michael addition/lactonisation cascade for the formation of ar ange of dihydropyridones 107 (Scheme 24 b). This was also extended for the synthesis of b-lactams on reactionw ith N-tosyl imine electrophiles, enabling the rapid formation of molecular complexity from feedstock chemicals with high efficiency.I tw as found that lower pressures of CO were beneficial for the reaction. Whilst higherC Op ressures favour CO insertion, high CO concentrations may limit oxidative addition and ketene formation by coordination to palladium. Catalyst 106 was identified as the optimal Lewis base catalyst, giving the products in higherd iastereo-a nd enantioselectivity.
Although powerful in concept, catalyst turnover by lactonisation/lactamisationh as limitations in terms of atom economy. When using carboxylic acid starting materials, pretreatment with stoichiometric amounts of activating agent and base is required to generate ar eactive mixed anhydride in situ prior to catalysta cylation.I na ddition, an electrophile with al atent nucleophilic site is necessary for catalystt urnover via intramolecular cyclisation, limiting these methodologies to the formation of cyclic products. To overcome these shortfalls, recentw ork has focusedo nanovel catalystt urnover methodu sing aryloxides that is exemplified in section3.

Catalyst Turnover via Aryloxide
Catalyst turnover via aryloxide relies on the intermoleculara ddition of an aryloxide nucleophile to the post-reaction acyl ammonium ion to complete the catalytic cycle (Section1, Scheme2right). One methodt oa chieve this is the inclusion of as toichiometric aryloxide as an additive. In 2014, Fu and coworkers utilised sodium pentafluorophenolate 111 as ac atalyst turnover agentf or the enantioselective fluorination of ketenes 108 using planar chiral DMAP catalyst 110 via aC (1)-ammonium enolatei ntermediate (Scheme 25 a). [63] However,t his approach requires the aryloxide to be compatible with other reagents, or,a si nt his case, the dropwise addition of reagents to avoid sidereactions.
Alternatively, the aryloxide can be catalytically generatedi n situ from ar eactionp artner.T hisw as first establishedi nc onjunction with C(1)-ammonium enolate intermediates in as eries of elegant manuscripts by Lecktaa nd co-workersf or enantioselectiveh alogenation. [10a, 64] Reaction of the C(1)-ammonium enolate( generated from ketenes) with ap olyhalogenated quinone electrophile 115 gave the acyl ammonium/aryloxide ion pair,w ith the aryloxide used for catalyst turnover (Scheme 25 b). Scheidt andc o-workers have developed ar elated "aryloxide rebound" concept in an NHC-catalysed formal Mannichp rocess. [65] Opposite to Lectka's strategy,i nt his case the aryloxide is generated from the nucleophilic reaction partner.U sing a-aryloxyaldehydes 118 as azoliume nolate precursors, the aryloxide generated in situ can react with the post-reaction acyl azolium ion to affect catalystt urnover (Scheme 25 c). It was proposed this approachcould be translated to reactions of C(1)-ammonium enolates throughu se of aryl ester enolate precursors.

Rearrangements of ammonium ylides
In 2014, Smith and co-workersr eported the isothiourea-promotedi ntramolecular [2,3]-sigmatropic rearrangement of allylic quaternary ammonium salts 124 to give stereodefined syn aamino acid derivatives 125 bearing two contiguous stereogenic centres in excellent yield and stereoselectivity (Scheme 26 a). [66] Key to optimal diastereo-and enantioselectivity was the addition of hydroxybenzotriazole (HOBt) as ac ocatalyst( 61 %y ield, 92:8 dr and 98:2 er without HOBt, vs. 76 % yield > 95:5 dr and > 99:1 er with HOBt). Various nucleophiles such as amines, alcohols and hydridesc ould be employed to give the corresponding amide, ester or alcohol products.T o circumvent the need for salt isolation,aone-pot allylic alkylation/[2,3]-rearrangementp rotocol was also developed, althought he products were isolated in diminished yield and enantioselectivity.S ubsequent experimental and computational studies were also carried out to probe the reactionm echanism in detail (Scheme26b). [67] Through extensive 13 Ca nd 15 N isotopic-labelling experiments and 13 C{ 1 H} NMR, post-rearrangement intermediate 126 was identified as ac atalystr esting state in the absence of HOBt. The addition of HOBt was found to shiftt he catalysts peciation toward the free catalyst, leading to increasedc atalyst concentrationi nt he reaction mixture. The beneficial effect of HOBt wast herefore proposed to origi-nate from ah igher concentration of free catalyst, enabling the enantioselectivep athway to better outcompete the racemic background reaction. Ther eactionm echanism is proposed to proceedb yd irect and reversible N-acylation of the catalyst by the para-nitrophenyl ester ammonium salt to give the acyl ammonium ion intermediate and release para-nitrophenoxide. Reversible deprotonation yields the ammonium ylide, which undergoes irreversible [2,3]-sigmatropic rearrangement to give post-rearrangement isothiouronium 126.T he rearrangementi s both stereo-and product determining. Catalyst turnover is achievedb ya ddition of HOBt to give the HOBt-ester in as econdary co-catalytic cycle, with reboundo ft he para-nitrophenoxide giving the ester product that is subsequently converted to the correspondinga mide by addition of an amine nucleophile. The observed stereoselectivity can be rationalised by an endo pretransitions tate assembly TS-IV where the ammonium ylide exhibits the expected stabilising n O to s* C-S interaction alongside an additional p-cation interaction between the allylic C(3)-aryls ubstituent and the acyl isothiouronium ion. [68] The rearrangement occurs from the opposite face to the stereodirecting phenylunit of the catalyst.

a-Functionalisation of esters:Synergistic catalysis
Snaddon and co-workers appliedt he aryloxidec atalystt urnover strategy for the enantioselective a-allylationofe sters enabled by dual catalysis. [56] In the presence of both (R)-benzotetramisole 9 and XantphosPd G3 140,arange of pentafluoro-phenyle sters 101 underwent enantioselective a-allylation with variousa llylic electrophiles 139 to give the corresponding linear a-functionalisede ster products 141 with excellent enantiocontrol (Scheme 30 a). The nature of the allylic leaving group had am arked effect on reactivity ande nantioselectivity; allylic esters and chlorides gave the allylationp roducts with poor enantioselectivity,whilst mesylate and tert-butylcarbonate leaving groups gave the products in high yield and er.P entafluorophenyl esters were found to be optimal for this dual-catalytic system,a llowing the products to be isolated in higher yield (due to increased chromatographic stability) and in shorter reaction times compared to other electron deficient aryl esters. The reaction mechanism for this process is proposed to involvet he union of the C(1)-ammonium enolatei ntermediate from the Lewis base nucleophilicc atalytic cycle( left) and the p-(allyl)Pd II electrophile generatedf rom the palladium cycle (right, Scheme 30 b). Critical to the success of merging these catalytic cycles is the reagent compatibilityo fe ach process; variation of either allylic nucleofuge,p alladium catalyst, Lewis base or electron deficient aryl ester has as ubstantial effect on the reaction outcome.
Buildingo nt his precedent, Snaddon and co-workersh ave broadened the scope of this methodology to reactions with a range of different electrophilic partnersb earing useful functional handlest hrough modification of the palladium catalyst system (Scheme 31). Using the same Lewis base isothiourea catalyst, the regioselective addition of C(1)-ammonium eno-lates, generatedf rom pentafluorophenyl esters 101,t oe lectron deficient allylic tosylate partners 139 such as a,b-unsatu-rated aldehydes,k etones, esters and amides has been achieved. [73] Interestingly,as ingle tris[tri(2-thienyl)phosphino]Pd 0 catalysts ystem was found to be broadly applicable for each carbonyl functionality,d espite discrepancies in electron-withdrawing character,d ipole and steric demand. Preliminary ligand studies indicated that the strong p-accepting character of the ligand facilitates the preference for syn p-(allyl)Pd II intermediates,l eading to regioselective (E)-alkenei somer formation.
Employing Pd 2 dba 3 and bidentate (S)-BINAP catalyst-ligand system in combination with (S)-BTM was found to be optimal for the addition of enolates to B(pin)-substituted allylic mesylate electrophiles. [74] Notably,m ismatched effects were observed when (R)-BINAP was used with (S)-BTM, where the enantioselectivity slightly decreased in this case. Aryl chlorides were toleratedi nt his process and did not undergo any competing Suzuki-Miyaura cross-coupling, whilst unproductivep rotodeboronation was also limited. B(MIDA)s ubstituted allylic electrophiles were also demonstrated to be suitable in this process.T he utility of the B(pin) substituent wasd emonstrated in ar ange of product derivatisations such as transesterification, CÀOc ross-coupling andS uzuki-Miyaura transformations. A Pd 2 dba 3 /P(2-furyl) 3 catalyst system was shown to enable the addition of C(1)-ammonium enolates to silicon substituted allylic mesylate partners to afford the linear ester products 144. [75] The P(2-furyl) 3 ligand was found to suppress competing addition of pentafluorophenolate to the allylic electrophile partner,w hichw as observed to limit the yield when other phosphine ligands were employed. The vinyl-silane functionality contained in the products was utilised in an array of derivatisations such as halogenation, Hiyama-Denmark cross-coupling and oxidation to the corresponding aldehyde.
In each previousc ase the linear allylated products were observed. Snaddon and co-workers postulated modulation of the palladium catalyst-ligand system from ab identate Xantphos ligand to am onodentate phosphine ligand would relieve steric congestion aroundt he metal centre and engage 2-substituted allyl partners. Indeed, ar ange of 2-substituted allylic mesylates 145 underwent reaction with the corresponding pentafluorophenyle sters 101 using am onodentate, sterically undemanding 2-thienyl phosphine ligand to give ar ange of branched aallylated esters 146 (Scheme 32 a). [76] The product esters could be isolated, or derivatised in situ by addition of an appropriate nucleophile (amine or hydride) at the end of the reactiont o give the corresponding amide or primary alcoholp roduct. DFT studies were carriedo ut to determine the natureo ft he transition state. This revealed ar elativelyl ow barrier( 12.2 kcal mol À1 ) for an outer-sphere attack of the enolateo nto the p(allyl)Pd complex, whereas an inner-sphere attack of ap alladium-ligated (Z)-enolate was found to be highly disfavoured (29.8 kcal mol À1 ).
Snaddona nd co-workersl ater extended the scope of this methodology to benzylic electrophiles. [77] Traditionally these are more challenging reaction partners due to the high energy of oxidative addition which requires dearomatisation of the arene unit. [78] Criticalt ot he success of this protocol was the identityo ft he nucleofuge (X): screening benzylic leaving groups revealed tosylate, acetate, tert-butylcarbonate were all unreactive, with only diphenylphosphate proving productive. Ar ange of benzylic phosphates 147 underwent reactionw ith pentafluorophenyle sters 101 in toluene catalysed by benzotetramisole 9 and Xantphosp alladium 140 (Scheme 32 b). Notably aw ider ange of functional groups are tolerated under the reaction conditions including bromide, alkyne and boron-containingf unctionality.The utility of this methodology wasshowcased in the synthesis of thrombin inhibitor DX-9065A. However,t he electrophilicp artner wasl imited to p-extended naphthyl groups.M onocyclic benzene-derived electrophiles were unreactivep resumablyd ue to higher dearomatisation energy.
Scheme33. Dual palladium/isothiourea-catalysede nantioselective a-allylation of 2-pyrrole substituted pentafluorophenyl esters. roles were tolerated, giving the corresponding allylated products in high yields with excellent enantioselectivity.Notably,n o undesired allylation of the electron rich pyrrole ring was observed. The analogousu nsubstitutedp yrrole derivative also gave the desired product with useful enantioselectivity.V arious allylic electrophile partners, in combination with the appropriate palladium catalysts ystem, could be employedf or the synthesis of both linear and brancheda llylated products, with excellent functional group tolerance demonstrated( Cl,B Pin, SiR 3 ). The synthetic utility of the pyrrole products was also highlighted throughat wo-step transesterification/ring closing metathesis sequence to form ab icycle pyrrole unit.
While Snaddon and co-workersh ave varied the palladium catalystt oa ddress reactivity challenges, Hartwig and co-workers sought to access complementary reactivity through use of an alternative metal catalyst. Thea uthors reported ar elated dual catalytic protocolu sing cooperative isothiourea/iridium catalysis, enabling exclusive formation of the branched allylated product. The enantioselective a-allylation of pentafluorophenyle sters 101 was achieved giving branched products 154 and 155 (Scheme 34). [80] This stereodivergent protocola llows access to all four product stereoisomers through predictable pairing of chiral catalyst enantiomers. Using each of the four differentc atalyste nantiomer combinations, each product stereoisomer could be isolated in high yield and in excellent dr and er,e xemplifying the highc ontrol each catalyst exhibits over the substrates. Benzotetramisole 9 governs the absolute configuration of the C(2)-carbon,w hilst the metallacyclic iridium complex [Ir] 153 determines the geometry,f acial selectivity and regioselectivity of the allyl electrophile, and therefore the absolute configurationa tC (3). Notably,i nt his case the reaction conditions remaina lmost identical to the protocold eveloped by Snaddon and co-workers. Through simple variation of only the metal catalyst, alternative reactivity has been achieved, highlighting the complementarity and potential of this synergistic methodology.Asimilaro bservation is also noticeable when comparingG ong and co-workersc arbonylation strategy (Scheme 24).
In 2019, Snaddon and co-workers soughtt op air the cooperative isothiourea/metal catalysis protocolw ith aH ofmann rearrangement [81] for the one-pot enantioselective synthesis of homoallylic amines. [82] It was proposed in situ conversion of the allylated ester products to the primarya mide could be ach-ieved using ammonia gas. Subsequentt reatment with an oxidant would enables tereospecific Hofmannr earrangementt o give the corresponding isocyanate, which could be quenched with an appropriate alcohol forming the carbamate-protected homoallylic amines (Scheme 35 a). Arange of pentafluorophenyl esters 101 and allylic electrophiles 150 successfully underwent the one-pot allylation-amidation-rearrangement procedure through treatment with ammonia gas at the end of the allylation reaction, followedb yo xidation using [bis(trifluoroacetoxy)iodo]benzene (PIFA). Both the linear (156)a nd branched (157)p roducts could be conveniently accessed in good yield with high enantioselectivities through simple choice of palladium or iridium catalysts, respectively (Scheme 35 b). This regio-and stereodivergent one-pot approach allows convenient and modulara ccess to av ariety of enantioenrichedh omoallylic amines. Notably,s imple variation of the alcohol allows various protected amines to be synthesised, and the addition of water allows formation of the free amine.

a-Functionalisation of esters:Alternative electrophiles
In 2018, using para-nitrophenyl esters 166 as C(1)-ammonium enolatep recursors, Smith and co-workersr eported the isothiourea-catalysed additiont ot etrahydroisoquinoline-derived iminium ions 165 (Scheme 36). [83] An appropriate amine nucleophile was added at the end of the catalytic reaction to convert the less stable para-nitrophenyl ester product to the corresponding amide. During the optimisation of this process addition of stoichiometric tetrabutylammonium para-nitrophenoxide 167 was shownt og ive increased yields and enantioselectivities.T his is proposed to increasep olarity of the reaction mixturew hilst also accelerating the rate of catalystt urnover. Also noteworthy was the effect that the iminium counterion had on product enantioselectivity.S mall, coordinating halides (Br À ,C l À )g ave highere nantioselectivities than larger,n on-coordinating anions such as BF 4 À ,P F 6 À and BPh 4 À .T he iminium bromide ions 165 could also be generated in situ via photoredox catalysis using BrCCl 3 and Ru(bpy) 3 Cl 2 ,a llowing for the de-velopment of ao ne-pots equential strategy.U sing this sequential photoredox/Lewis base-catalysed procedure, ar ange of para-nitrophenyl esters 166 could be converted to the bamino amide products 168 in good yield with high enantioselectivity,but with low diastereoselectivity (= 75:25 dr). This process overcomes some of the challenges associated with aryloxide catalyst turnover such as compatibilityo fn ucleophilic (aryloxide,L ewis base catalyst) and electrophilic species (iminium ion) within the reaction mixture.
These impressive methodologiesu sing aryloxide catalyst turnover have significantly broadened the reaction scope, showcasing the reaction of C(1)-ammonium enolate intermediates in dual-catalytic processes andw ith alternative electrophiles for the enantioselective a-functionalisation of acyclic esters. However,i nt hese previousp rocesses there is at ypical requirement for relativelyh igh catalystl oadings (often 20 mol %) and/or excess auxiliary Brønsted base (necessary to neutralise acidic by-products) for effective reactivity.I na ddition, these processes had not been investigatedt oi dentify reaction intermediates, orders with respect to each component and turnoverl imiting steps.
In 2019, Smith and co-workersd eveloped ab ase-free protocol for the enantioselective a-functionalisation of esters (Scheme 37 a). [84] Reaction of ar ange of para-nitrophenyl esters 166 with vinyl bis-sulfone Michael acceptors 169 catalysed by only 5mol %( R)-benzotetramisole 9 gave a-alkylated para-nitrophenyl ester and amide products 170 (after derivatisation) in excellent yield and stereoselectivity.K ey to the success of this methodology was the multifunctional aryloxide whicho perates as al eaving group, Brønsted base, Brønsteda cid (as the corresponding phenol)a nd as aL ewis base within the catalytic cycle, allowing for the reaction to be carried out in the absence of an auxiliary base. The steric and electronic natureo f the aryloxide was assessed. It was concluded that esters derived from phenols with al ower pK a value (pentafluorophenyl, tetrafluorophenyl) [85] gave decreased reactivity,w hilst esters of higher pK a -s uch as the ester derived from phenol-w erec ompletely unreactive. The ester derived from para-nitrophenol, whose pK a lies between these two extremes, [86] gave optimal yields. This is proposed to be due to ac areful balance of leaving group ability,a mphoteric behaviour and steric effects, [87] where para-nitrophenol is the most effective aryloxide fort his application.T he reaction was also demonstrated to be functional in environmentally benign solvents such as dimethylcarbonate, isopropyl acetate and 2-methyl THF. [88] The functional products could be deprotected upon treatment with magnesium turningst of orm a-alkylated amides without loss of enantiopurity. The pronucleophilic nature of the sulfone functional handle was also exploited under basic conditions in the presence of benzyl bromide or methyl vinyl ketone to provide chain extended amides.
Comprehensive mechanistic investigationsw ere carried out to interrogate the reaction mechanism.Q uantitative 19 F{ 1 H} NMR was employed for reaction monitoring andt o identify the catalyst resting state (free catalyst) and deactivation through protonation. When employed in tandem with variable time normalisation analysis (VTNA) [41] the reactiono rders with respect to each component were determined.T he ester, vinyl bis-sulfone and catalyst were all determined to be first order,i ndicating the turnover limiting step involved each component, and was either Michael addition or catalystt urnover.A competition reaction between proto-vinyl bis-sulfone 171 and deutero-vinyl bis-sulfone 172 revealed an inverse secondary kinetic isotope effect (Scheme 37 b), confirming the Michael addition as the turnover limiting step. Product inhibition was also observedd uring the mechanistic analysis. It is proposed the acidic proton within the product (adjacent to sulfonyl groups) may inhibit the reaction by protonating either the C(1)-ammonium enolate or aryloxide, thus retarding the rate of catalyst turnover.
The reaction mechanism was proposed to proceed by reversible N-acylation of benzotetramisole catalyst I with ester II to form acyl ammoniumi on pair III (Scheme38). Reversible deprotonation of the acyl ammonium ionb ythe aryloxide counter anion affords the nucleophilic C(1)-ammonium enolate IV and releases para-nitrophenol. Turnover limiting Michael addition to the electrophile V on the Re face of the enolatel eads to intermediate VI.P rotonation by the para-nitrophenol released in step two gives acyl ammonium ion pair VII.A ddition of the aryloxidea nion forms the product VIII and regenerates catalyst I,w hich is in equilibrium with the catalytically inactive protonated-BTM IX.T he observedd iastereoselectivity can be rationalised tentatively by af avoured open pre-transition state assembly TS-V where gauche interactions are minimised about the forming CÀCb ondw hile allowing ap otentially favourable p-cationi nteraction between the b-substituent of the bis-sulfone electrophile and the isothiouronium cation. [68] The relative configuration within the major diastereoisomero btained using these bis-sulfone electrophiles is oppositet ot hat observed in previous isothiourea catalysis employing intramolecular catalyst turnover processes and in the intermoleculara ddition to iminium ions. This differencec an presumably be rationalised due to the two highly sterically demandings ulfone groups of this series of electrophile. Whilst this process enablest he generationo faC(1)-ammonium enolate withoutt he requirement for use of an excessa uxiliary base, ac learl imitation is the use of ah ighly reactive vinyl bis-sulfone Michael acceptors. Electrophiles bearing only one sulfonyl electron-withdrawing group were unreactive in this protocol. Therefore, am ore general solution remains elusive.
Employing as imilars trategy to Song andc o-workers, [45] Han and co-workersr eported the enantioselective protonation of C(1)-ammonium enolates generated from a-diazoketones through av isible-light-induced ketene formation (Scheme 39). [89] The transformationi sp roposed to proceed through Wolff rearrangemento fa-diazoketones to give disubstitutedk etenes,w hich can be intercepted by aL ewis base to give the disubstituted C(1)-ammonium enolate. Protonation and catalystt urnover by ac orresponding phenol gives access to a,a-disubstituted carboxylic esters (Scheme 39 a). Ar ange of a-aryl-a-diazoalkylketones 70 smoothly underwent the rearrangement/enantioselective protonation sequence when treated with phenol 177 andi sothiourea catalyst 178 under blue LED irradiation to give the corresponding a-alkyl-a-aryl-ester products 179 (Scheme 39 b). The method was also used to prepare (R)-ibuprofen in two steps from the corresponding a-diazoketones and phenol 177.S ubstitution in the 2-position with an electron-donating group, and an electron-withdrawing group in the 4-position of the phenol is required for high enantioselectivities.

Conclusions and Outlook
C(1)-Ammonium enolates are effective and versatile synthetic intermediates for enantioselective a-functionalisation of carbonyl units at the carboxylic acid oxidation level. In recent years, new methods for generating C(1)-ammonium enolates from different precursors have been developedu sing acyl imidazoles,e lectron deficient aryl esters and a-diazoketones. Through catalystt urnover by lactonisation/lactamisation, many enantioenriched chiral heterocycles can be prepared efficiently. Enantioselective a-functionalisationo fa cyclice sters has been recently achieved by employing electron deficient aryl esters as enolatep recursors. Advances in catalyst design have also been achieved through the application of immobilised catalysts and isoselenoureas. Despite these advances, many opportunities remainf or the developmento fn ovel reactions, particularly with aryloxide catalystt urnover which has been less explored but is an expanding research area. Applicationf or the synthesis of complex target moleculesa nd use in industry is desirable, especiallyo wing to the mild reactionc onditions and functional group tolerance. Reactivity limitations remain,s uch as the general need for an aryl or alkenyl substituent in the aposition. In addition, access to disubstituted enolates for the synthesis of quaternary centres remains limited. The majority of examples involvethe addition to sp 2 -hybridised carbon electrophiles. Whilst Lectka has demonstrated CÀXb onds can be formed via C(1)-ammonium enolate intermediates,t his process uses acid chloride/ketene starting materials. Expansion of compatible electrophiles in combination with aryloxide catalyst turnoveru sing aryl ester precursorst of orm CÀXb onds would also be clearly beneficial. Finally,acontinued advancement to more sustainable, atom-economical processes using environ-mentallyf riendly solvents would make the area more appealing for industrialists.